First-in-human phase 1 dose escalation study of the KAT6 inhibitor PF-07248144 in patients with advanced solid tumors.
Authors: David Sommerhalder, Erika P. Hamilton, Toru Mukohara, Kan Yonemori, Monica M. Mita, Toshinari Yamashita, Jenny Zheng, LI Liu, Arnab K. Maity, Natasha Homji Mishra, Orlaith Bogg, Meng Li, Patricia LoRusso
Journal: Journal of Clinical Oncology (2023)

1054 Background: KAT6A and KAT6B regulate gene transcription via acetylation of histone H3K23 and their dysregulation drives lineage-specific gene expression in cancer. We report dose escalation data from the first-in-human phase 1 (Part 1A and 1B; NCT04606446) study of the KAT6-selective inhibitor PF-07248144. Methods: Part 1A (monotherapy dose escalation) enrolled patients (pts) with advanced/metastatic ER+/HER2− breast cancer (mBC), CRPC, or NSCLC, resistant/intolerant to standard therapy. Part 1B (PF-07248144 + fulvestrant combination dose escalation) enrolled pts with advanced/metastatic ER+/HER2- mBC with disease progression after ≥1 line of CDK4/6 inhibitor and endocrine therapy (ET). PF-07248144 (1-15 mg in Part 1A) was administered orally once per day (QD) in 28-day cycles following Bayesian design with overdose control. Study objectives: primary - assess PF-07248144 safety and tolerability, including dose limiting toxicities (DLT); secondary - evaluate PF-07248144 pharmacokinetics (PK); and exploratory - evaluate pharmacodynamics (PD; peripheral blood mononuclear cells [PBMC] and tumor H3K23Ac inhibition) and antitumor activity (using RECIST 1.1 by investigator assessment). Results: At data cut off (30 Sep 2022), 29 pts were enrolled: 25 in Part 1A (12 mBC, 11 CRPC, 2 NSCLC) and 4 in Part 1B (mBC). Part 1A evaluated 5 dose levels (1-15 mg QD) and Part 1B evaluated 5 mg PF-07248144 QD + 500 mg fulvestrant. Median age across Part 1A and 1B was 67 yrs (range 48-90). A total of 83% (Part 1A) and 75% (Part 1B) of pts with mBC had received &gt; 3 prior lines of systemic anticancer therapy. Three DLTs (Grade 3 [G3] neutropenia) were observed: 2 in Part 1A (8 mg and 2 mg QD) and 1 in Part 1B (5 mg QD). A maximum tolerated dose was not identified; 5 mg QD was identified as the recommended dose for expansion for both monotherapy and fulvestrant combination. Across Parts 1A and 1B, treatment-related AEs (TRAEs; any grade) in ≥20% pts were dysgeusia (72%), anemia (52%), neutropenia (48%), thrombocytopenia (31%), diarrhea (31%), white blood cells (WBC) decreased (28%), fatigue (24%), and aspartate aminotransferase increased (21%); the majority of TRAEs were G1-2. TRAEs ≥G3 seen in &gt; 1 pt were neutropenia (6/29; 21%), anemia (5/29; 17%), and WBC decreased (2/29; 7%). PF-07248144 PK was linear between 1 and 15 mg. H3K23Ac inhibition (≥70%) in PBMCs was achieved at steady state at doses of ≥1 mg. Tumor H3K23Ac levels were reduced by &gt; 50% in 4 paired tumor biopsies at exposures associated with preclinical anti-tumor activity. Confirmed and durable partial responses were observed in 1/8 (Part 1A) and 2/4 (Part 1B) response-evaluable pts with ER+/HER2- mBC who progressed on prior ET+CDK4/6 inhibitor treatment. Conclusions: PF-07248144 was well tolerated and associated with strong KAT6 inhibition in PBMCs and tumors and confirmed partial responses in pts with heavily treated ER+/HER2- mBC during dose escalation. Clinical trial information: NCT04606446 .